Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. KG Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Cancer Res. 2015 Feb 15;75(4):698-708. doi: 10.1158/0008-5472.CAN-14-2637. Epub 2015 Feb 3.
TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to significantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both refines our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool.
TP53 基因突变与乳腺癌预后不良相关，但需要额外的生物标志物来进一步细化 p53 通路的影响，以实现临床应用。在这项研究中，我们基于其与其他抑制性突变的关联，评估了 HDMX-S/FL 比值作为此类生物标志物的作用，这些突变在肉瘤（另一种受 p53 监测的癌症）中赋予更差的预后。我们发现，HDMX-S/FL 比值与 p53 突变状态相互作用，可显著改善乳腺癌患者的预后能力。该生物标志物对与基于微阵列的预后测定相当。出乎意料的是，该效用与 DNA 损伤治疗无关，而是与不同的肿瘤转移潜能有关。最后，我们获得了证据表明，该生物标志物对可能可以识别出受益于抗 HDM2 策略以阻止转移进展的患者。总之，我们的工作提供了一个 p53 通路标志物，它不仅细化了我们对 p53 活性对预后影响的理解，而且具有作为临床工具的潜在效用。
